Disruption of microRNA biogenesis confers resistance to ER stress-induced cell death upstream of the mitochondrion.

Global downregulation of microRNAs (miRNAs) is a common feature of human tumors and has been shown to enhance cancer progression. Several components of the miRNA biogenesis machinery (XPO5, DICER and TRBP) have been shown to act as haploinsufficient tumor suppressors. How the deregulation of miRNA b...

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Autores principales:	Karen Cawley, Susan E Logue, Adrienne M Gorman, Qingping Zeng, John Patterson, Sanjeev Gupta, Afshin Samali
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4145669fbed445928aa3b8e5b672123d
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spelling	oai:doaj.org-article:4145669fbed445928aa3b8e5b672123d2021-11-18T08:58:55ZDisruption of microRNA biogenesis confers resistance to ER stress-induced cell death upstream of the mitochondrion.1932-620310.1371/journal.pone.0073870https://doaj.org/article/4145669fbed445928aa3b8e5b672123d2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23977393/?tool=EBIhttps://doaj.org/toc/1932-6203Global downregulation of microRNAs (miRNAs) is a common feature of human tumors and has been shown to enhance cancer progression. Several components of the miRNA biogenesis machinery (XPO5, DICER and TRBP) have been shown to act as haploinsufficient tumor suppressors. How the deregulation of miRNA biogenesis promotes tumor development is not clearly understood. Here we show that loss of miRNA biogenesis increased resistance to endoplasmic reticulum (ER) stress-induced cell death. We observed that HCT116 cells with a DICER hypomorphic mutation (Exn5/Exn5) or where DICER or DROSHA were knocked down were resistant to ER stress-induced cell death. Extensive analysis revealed little difference in the unfolded protein response (UPR) of WT compared to Exn5/Exn5 HCT116 cells upon ER stress treatment. However, analysis of the intrinsic apoptotic pathway showed that resistance occurred upstream of the mitochondria. In particular, BAX activation and dissipation of mitochondrial membrane potential was attenuated, and there was altered expression of BCL-2 family proteins. These observations demonstrate a key role for miRNAs as critical modulators of the ER stress response. In our model, downregulation of miRNA biogenesis delays ER stress-induced apoptosis. This suggests that disrupted miRNA biogenesis may contribute to cancer progression by inhibiting ER stress-induced cell death.Karen CawleySusan E LogueAdrienne M GormanQingping ZengJohn PattersonSanjeev GuptaAfshin SamaliPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 8, p e73870 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Karen Cawley Susan E Logue Adrienne M Gorman Qingping Zeng John Patterson Sanjeev Gupta Afshin Samali Disruption of microRNA biogenesis confers resistance to ER stress-induced cell death upstream of the mitochondrion.
description	Global downregulation of microRNAs (miRNAs) is a common feature of human tumors and has been shown to enhance cancer progression. Several components of the miRNA biogenesis machinery (XPO5, DICER and TRBP) have been shown to act as haploinsufficient tumor suppressors. How the deregulation of miRNA biogenesis promotes tumor development is not clearly understood. Here we show that loss of miRNA biogenesis increased resistance to endoplasmic reticulum (ER) stress-induced cell death. We observed that HCT116 cells with a DICER hypomorphic mutation (Exn5/Exn5) or where DICER or DROSHA were knocked down were resistant to ER stress-induced cell death. Extensive analysis revealed little difference in the unfolded protein response (UPR) of WT compared to Exn5/Exn5 HCT116 cells upon ER stress treatment. However, analysis of the intrinsic apoptotic pathway showed that resistance occurred upstream of the mitochondria. In particular, BAX activation and dissipation of mitochondrial membrane potential was attenuated, and there was altered expression of BCL-2 family proteins. These observations demonstrate a key role for miRNAs as critical modulators of the ER stress response. In our model, downregulation of miRNA biogenesis delays ER stress-induced apoptosis. This suggests that disrupted miRNA biogenesis may contribute to cancer progression by inhibiting ER stress-induced cell death.
format	article
author	Karen Cawley Susan E Logue Adrienne M Gorman Qingping Zeng John Patterson Sanjeev Gupta Afshin Samali
author_facet	Karen Cawley Susan E Logue Adrienne M Gorman Qingping Zeng John Patterson Sanjeev Gupta Afshin Samali
author_sort	Karen Cawley
title	Disruption of microRNA biogenesis confers resistance to ER stress-induced cell death upstream of the mitochondrion.
title_short	Disruption of microRNA biogenesis confers resistance to ER stress-induced cell death upstream of the mitochondrion.
title_full	Disruption of microRNA biogenesis confers resistance to ER stress-induced cell death upstream of the mitochondrion.
title_fullStr	Disruption of microRNA biogenesis confers resistance to ER stress-induced cell death upstream of the mitochondrion.
title_full_unstemmed	Disruption of microRNA biogenesis confers resistance to ER stress-induced cell death upstream of the mitochondrion.
title_sort	disruption of microrna biogenesis confers resistance to er stress-induced cell death upstream of the mitochondrion.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/4145669fbed445928aa3b8e5b672123d
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Disruption of microRNA biogenesis confers resistance to ER stress-induced cell death upstream of the mitochondrion.

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